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Preview: Chirality


Wiley Online Library : Chirality

Published: 2018-03-01T00:00:00-05:00


Novel chiral ionic liquids stationary phases for the enantiomer separation of chiral acid by high-performance liquid chromatography


Novel chiral ionic liquid stationary phases based on chiral imidazolium were prepared. The ionic liquid chiral selector was synthesized by ring opening of cyclohexene oxide with imidazole or 5,6-dimethylbenzimidazole, and then chemically modified by different substitute groups. Chiral stationary phases were prepared by bonding to the surface of silica sphere through thioene “click” reaction. Their enantioselective separations of chiral acids were evaluated by high-performance liquid chromatography. The retention of acid sample was related to the counterion concentration and showed a typical ion exchange process. The chiral separation abilities of chiral stationary phases were greatly influenced by the substituent group on the chiral selector as well as the mobile phase, which indicated that, besides ion exchange, other interactions such as steric hindrance, π-π interaction, and hydrogen bonding are important for the enantioselectivity. In this report, the influence of bulk solvent components, the effects of varying concentration, and the type of the counterion as well as the proportion of acid and basic additives were investigated in detail.

Chiroptical spectroscopy and metabolomics for blood-based sensing of pancreatic cancer


To enable the early diagnosis of pancreatic cancer, the search for and definition of reliable biomarkers remain a subject of great interest, with the specificity and sensitivity of the currently used biomarkers being below the required values. We tested a novel diagnostic approach for pancreatic cancer based on the specific molecular signature of blood plasma components. To acquire more detailed structural information, structure-sensitive chiroptical methods (electronic circular dichroism and Raman optical activity) were supplemented by conventional Raman and infrared spectroscopies. The obtained spectra were subsequently processed by linear discriminant analysis yielding high values of specificity and sensitivity. In addition, to monitor not only large biomolecules as potential biomarkers but also those of low molecular weight, we conducted an analysis of blood plasma samples by using metabolomics. The achieved results suggest a panel of promising biomarkers for a reliable detection of pancreatic cancer. A unique diagnostic approach for pancreatic cancer is proposed. Using chiroptical and vibrational spectroscopies, we were able to reveal disease-specific spectral patterns. Moreover, several molecules not yet linked to pancreatic cancer were identified by metabolomics.

Analysis of stereoisomers of chiral drug by mass spectrometry


Chiral molecules are of great importance in the life science since individual enantiomers may differ in biological activity, mechanism, and toxicity, making it necessary to explore efficient chiral analysis methods. Chromatography approaches are often used to differentiate enantiomers while mass spectrometry (MS) was thought to be blind in chiral analysis. With the development of MS technique, it began to play a more and more crucial part in chiral observation. In this review, we will give a detailed introduction of the analysis methods related to MS for chiral drugs, including its mechanism, applications, and future development.

Polarization in France


The special relationship between France and the polarization of light from the beginning of the 19th century until the present day is reviewed in the lives and works of Étienne Louis Malus, François Arago, Jean-Baptiste Biot, Augustin Fresnel, Louis Pasteur, Frédéric Wallerant, Aimé Cotton, Francis Perrin, and Alain Aspect. To avoid a redundant presentation of information that can be found with an Internet search engine, the author emphasizes how the aforementioned individuals have influenced the studies of stereochemistry, molecular chirality, and the polarization of light in his research group. Aimé Cotton's circular dichroism apparatus. From Recherches sur l'absorption et la dispersion de la lumière par les milieux doués du pouvoir rotatoire. J. Phys. Theor. Appl. 1896:5:237-244.

Electronic circular dichroism for the detection of microalbuminuria


Over the past decades, chiroptical spectroscopy has proved its incomparable ability to elucidate the structure and spatial arrangement of chiral molecules. Systematic analysis of biomolecules in the natural environment of biofluids, however, remains challenging. In this study, we used chiroptical spectroscopy to monitor urinary levels of human serum albumin. Not only severe proteinuria but even just a slightly increased urinary excretion of albumin (microalbuminuria) may indicate serious health complications, especially for diabetic individuals. Given the chiral nature of albumin and its typical spectral pattern, it may be easily observable by chiroptical spectroscopy, particularly electronic circular dichroism. The performed chiroptical analysis of urine not only allowed the detection of clinically confirmed microalbuminuria but was also able to reveal this pathological condition in cases beyond the diagnostic capability of common clinical procedures. Thus, our approach suggests that electronic circular dichroism is a useful tool for the fast and reliable qualitative monitoring of microalbuminuria with the potential for a quantitative analysis in the future. We present a novel application of chiroptical spectroscopy, specifically electronic circular dichroism to analyze urine for the detection of human serum albumin. Not only severe proteinuria but even just a slightly increased urinary excretion of albumin (microalbuminuria) may indicate serious health complications, especially for diabetic patients. Our approach suggests electronic circular dichroism as a useful tool for the fast and reliable qualitative monitoring of microalbuminuria with the potential for a quantitative analysis in the future.

Comprehensive investigation into the interconversion of C-2 diastereomers of naringin


Naringin is a flavanone that widely presents on daily diet and traditional medicinal materials. The ratios of naringin C-2 diastereomers are found different in reported samples, thus suspiciously leading to various functions. In this study, we measured the interconversion of C-2 diastereomers intensively with ultimate high-performance liquid chromatography and circular dichroism spectra. We examined the diastereomeric naringins in fresh citrus fruit, Huajuhong decoction pieces, and naringin tablet; evaluated the impact of tablet production procedures in factory; and monitored the rapid racemization in incubation. The results not only confirmed that enzyme, temperature, and pH condition could influence the interconversion but also demonstrated that diverse ratios of diastereomers showed limited influence on metabolic behaviors of naringin in the blood, which consequently cause comparable bioactivities. This study could provide comprehensive understanding of diastereomeric interconversion and provide useful reference for drug development.

Chiral molecules adsorbed on a solid surface: Tartaric acid diastereomers and their surface explosion on Cu(111)


The adsorption of diastereoisomers of tartaric acid, namely, meso (R,S)-tartaric acid, (R,R)-tartaric acid, and the racemic mixture of (R,R) and (S,S) tartaric acid on the (111) surface of a copper single crystal has been studied by means of reflection-absorption IR Spectroscopy, X-ray photoelectron spectroscopy, low-energy electron diffraction, and thermal desorption spectroscopy. Two distinct adsorption modes are identified for all three adsorbate systems. All molecules undergo an identical thermally induced autocatalytic decomposition reaction above 510 K. The pure enantiomers show 2D chiral long-range ordered structures of opposite handedness.

Tetrathiafulvalene-[2.2]paracyclophanes: Synthesis, crystal structures, and chiroptical properties


Two racemic tetrathiafulvalene-[2.2]paracyclophane electron donors EDT-TTF-[2.2]paracyclophane 1 and (COOMe)2-TTF-[2.2]paracyclophane 2 have been synthesized via the phosphite mediated cross coupling strategy. Chiral HPLC allowed the optical resolution of the (RP) and (SP) enantiomers for both compounds. Solid-state structures of (RP)-1 and (rac)-2 have been determined by single crystal X-ray analysis. Intermolecular π-π and S•••S interactions are disclosed in the packing. Single crystal X-ray analysis of (RP)-1 combined with experimental and theoretical circular dichroism spectra allowed the assignment of the absolute configuration of the enantiomers of 1 and 2.

Structure determination of butylone as a new psychoactive substance using chiroptical and vibrational spectroscopies


Recently, there has been a worldwide substantial increase in the consumption of new psychoactive substances (NPS), compounds that mimic the structure of illicit drugs, such as amphetamines or ecstasy. The producers try to avoid the law by a slight modification of illicit structures, thereby developing dozens of temporarily legal NPS every year. The current trends in the detection and monitoring of such substances demand a fast and reliable analysis. Molecular spectroscopy represents a highly effective tool for the identification of NPS and chiroptical methods can provide further information on their 3D structure, which is the key for the determination of their biological activity. We present the first systematic study of NPS, specifically butylone, combining chiroptical and vibrational spectroscopies with ab initio calculations. According to density functional theory calculations, 6 stable lowest energy conformers of butylone were found and their molecular structure was described. For each conformer, the relative abundance based on the Boltzmann distribution was estimated, their population weighted spectra predicted and compared to the experimental results. Very good agreement between the experimental and the simulated spectra was achieved, which allowed not only the assignment of the absolute configuration, but also a precise description of the molecular structure.

Chiroptical and vibrational spectroscopic study of genuine and counterfeit medicines containing tadalafil


The production and distribution of counterfeit pharmaceuticals present a serious problem worldwide. This is true especially in case of phosphodiesterase type 5 inhibitors for treating erectile dysfunction, where consumers often prefer buying them anonymously from unverified sources. In this study, genuine and counterfeit Cialis® 20 mg tablets were analyzed by electronic circular dichroism, vibrational circular dichroism, and infrared spectroscopy. The characteristic spectral patterns were identified by comparison with the spectra of tadalafil standard as an active pharmaceutical ingredient, and its presence was confirmed in all samples. The amount of tadalafil, however, was markedly lower in the case of counterfeit tablet as the observed band intensities were considerably lower. No other significant differences between the genuine and counterfeit tablets were revealed. Ab initio density functional theory calculations provided a detailed description of the stable conformers of tadalafil in a solution and enabled thorough interpretation of the experimental spectra. This is the first study where electronic circular dichroism and vibrational circular dichroism spectroscopies were applied for an analysis of real Cialis® 20 mg tablets containing chiral tadalafil. The counterfeit was convincingly recognized from the genuine preparation as the amount of the active substance was significantly lower than that declared by the producer. Moreover, the 3D structure of tadalafil in a solution was described and the experimental spectra were subjected to a detailed interpretation based on density functional theory calculations.

Comparison of measured and predicted specific optical rotation in gas and solution phases: A test for the polarizable continuum model of solvation


A comparative theoretical and experimental study of dispersive optical activity is presented for a set of small, rigid organic molecules in gas and solution phases. Target species were chosen to facilitate wavelength-resolved measurements of specific rotation in rarefied vapors and in organic solvents having different polarities, while avoiding complications due to conformational flexibility. Calculations were performed with two density functionals (B3LYP and CAM-B3LYP) and with the coupled-cluster singles and doubles (CCSD) ansatz, and solvent effects were included through use of the polarizable continuum model (PCM). Across the various theoretical methods surveyed, CCSD with the modified velocity gauge provided the best overall performance for both isolated and solvated conditions. Zero-point vibrational corrections to equilibrium calculations of chiroptical response tended to improve agreement with gas-phase experiments, but the quality of performance realized for solutions varied markedly. Direct comparison of measured and predicted specific-rotation suggests that PCM, in general, is not able to reproduce attendant solvent shifts (neither between gas and solution phases nor among solvents) and fares better in estimating actual medium-dependent values of this property (although the error is rather system dependent). Thus, more elaborate solvation models seem necessary for a proper theoretical description of solvation in dispersive optical activity.

Modifying oligoalanine conformation by replacement of amide to ester linkage


Oligo(lactic acid) is an ester-analogue of short oligoalanine sequence and adopts a rigid left-handed helical structure. In this study, oligo(lactic acid) was incorporated into oligoalanine sequences and their conformations were studied by vibrational circular dichroism and electronic circular dichroism spectroscopy. The results suggested that oligo(lactic acid) moiety in these sequences maintains a left-handed helix and increases the conformational propensity of the oligoalanine moiety to form a left-handed polyproline type II-like helix. The importance of the chirality of oligo(lactic acid) moiety for the oligoalanine conformation was also studied. The results obtained in this study should be useful in developing ester-containing oligopeptides that function better than normal peptides.

On the chiroptical properties of racemic crystals


In a recent letter on the “Optical activity from racemates”, discussed at the 16th International Conference on Chiroptical Spectroscopy in Rennes (June 2017), scientists claimed to have measured the circular dichroism of colored, racemic crystals of two transition metal complexes, observations that “serve to correct a clear deficit in our understanding of the optical properties of racemates.” In fact, there is no deficit in our understanding of the optical properties of racemates. Moreover, the measurements presented are unconvincing as evidence of circular dichroism measured in anisotropic crystals and therefore do not inform our understanding of the specific crystals investigated, or racemates generally speaking.

Study on the HPLC-based separation of some ezetimibe stereoisomers and the underlying stereorecognition process


The enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different chiral stationary phases, ie, 3 polysaccharide-based chiral columns, was studied. It was observed that cellulose-based Chiralpak IC column exhibited the best resolving ability. After the optimization of mobile phase compositions in both normal and reversed phase modes, satisfactory separation could be obtained on Chiralpak IC column, especially in normal phase mode. The use of prohibited solvents as nonstandard mobile phase gave rise to better resolution than that of standard mobile phases (n-hexane/alcohol system). In addition, the presence of ethanol in nonstandard mobile phase has played an important role in enhancing chromatographic efficiency and resolution between ezetimibe stereoisomers. Various attempts were made to comprehensively compare the chiral recognition capabilities of immobilized versus coated polysaccharide-based chiral columns, amylose-based versus cellulose-based chiral stationary phases, reversed versus normal phase modes, and standard versus nonstandard mobile phases. Moreover, possible solute-mobile phase-stationary phase interactions were derived to explain how stationary and mobile phases affected the separation. Then the method validation with respect to selectivity, linearity, precision, accuracy, and robustness was carried out, which was demonstrated to be suitable and accurate for the quantitative determination of (RRS)-ezetimibe impurity in ezetimibe bulk drug. Enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different polysaccharide-based chiral columns (Chiralpak AD-H, Chiralcel OD-RH, and Chiralpak IC) was studied with suitable mobile phases compositions. Attempts were made to comprehensively compare the chiral recognition capabilities of immobilized versus coated polysaccharide-based chiral columns, amylose-based versus cellulose-based chiral stationary phases, reversed versus normal phase modes, and standard versus nonstandard mobile phases. Then, the method was validated for the quantitative determination of (RRS)-ezetimibe impurity in ezetimibe bulk drug.

Mutual inversion of flurbiprofen enantiomers in various rat and mouse strains


Flurbiprofen (F) is a nonsteroidal anti-inflammatory drug (NSAID) used therapeutically as the racemate of (R)-enantiomer and (S)-enantiomer. The inversion of RF to SF and vice versa was investigated in C57Bl/6 and SJL mice and Dark Agouti and Lewis rats. The enzyme α-methylacyl-CoA racemase (AMACR) is involved in the chiral inversion pathway that converts members of the 2-arylpropionic acid NSAIDs from the R-enantiomer to the S-enantiomer. We studied C57Bl/6 mice deficient in AMACR postulating that they should show reduced inversion of RF to SF. In line with the data of others in mice, (R)-inversion to (S)-inversion was relatively high in both the C57Bl/6 and SJL mice (fraction inverted, FI = 37.7% and 24.7%, respectively). In contrast, in AMACR deficient mice, there was no measurable peak for SF after administration of RF. The results in both rat strains (Dark Agouti and Lewis rats, FI = 1.4% and 4.1%, respectively) confirm the low chiral inversion of the enantiomers of flurbiprofen in the rat, as observed by other authors in the Sprague-Dawley strain (<5%). From the present results, we conclude that for the study of flurbiprofen enantiomers, the rat is more suitable than the mouse as a model for the human in which (R)-inversion to (S)-inversion is negligible.

Validation of molecular force field parameters for peptides including isomerized amino acids


Recently, stereoinversions and isomerizations of amino acid residues in the proteins of living beings have been observed. Because isomerized amino acids cause structural changes and denaturation of proteins, isomerizations of amino acid residues are suspected to cause age-related diseases. In this study, AMBER molecular force field parameters were tested by using computationally generated nonapeptides and tripeptides including stereoinverted and/or isomerized amino acid residues. Energy calculations by using density functional theory were also performed for comparison. Although the force field parameters were developed by parameter fitting for l-α-amino acids, the accuracy of the computational results for d-amino acids and β-amino acids was comparable to those for l-α-amino acids. The conformational energies for tripeptides calculated by using density functional theory were reproduced more accurately than those for nonapeptides calculated by using the molecular mechanical force field. The evaluations were performed for the ff99SB, ff03, ff12SB, and the latest ff14SB force field parameters.

Conformation change of hornet silk proteins in the solid phase in response to external stimulation


Hornet silks adopt a variety of morphology such as fibers, sponge, films, and gels depending on the preparation methods. We have studied the conformation change of hornet silk proteins (Vespa mandarina) as regenerated films, using chiroptical spectrophotometer universal chiroptical spectrophotometer 1, which can measure true circular dichroism spectra without artifact signals that are intrinsic to solid-state samples. The spectra showed that the proteins in films alter the conformation rapidly from the α-helix to the coiled coil and then to a β-sheet structure in response to heat/moisture treatment, but the transformation stopped at the coiled coil state when the sample was soaked in EtOH/water solution. Water is required for the α-helix to the coiled coil transition, and extra energy is required for the further transition to a β-sheet structure. This is the first successful circular dichroism study of fibril silk proteins to follow the conformation changes in the solid state. This work shows that proteins can undergo conformational changes easily even in the solid phase in response to external stimuli, and this can be traced by solid-phase-feasible chiroptical spectrophotometers. Application of unnatural stress to proteins gives valuable insights into their structure and characteristics. Hornet silks adopt a variety of morphology such as fibers, sponge, films, and gels depending on the preparation methods. We have shown that by using a special chiroptical spectrophotometer that can remove erroneous signals from macroscopic anisotropies of solid samples, universal chiroptical spectrophotometer 1, the proteins change the secondary structure easily in the solid state in response to external stimulation (eg, steam), from α-helix to coiled coil and then to β-sheet.

The resolution of acyclic P-stereogenic phosphine oxides via the formation of diastereomeric complexes: A case study on ethyl-(2-methylphenyl)-phenylphosphine oxide


As an example of acyclic P-chiral phosphine oxides, the resolution of ethyl-(2-methylphenyl)-phenylphosphine oxide was elaborated with TADDOL derivatives, or with calcium salts of the tartaric acid derivatives. Besides the study on the resolving agents, several purification methods were developed in order to prepare enantiopure ethyl-(2-methylphenyl)-phenylphosphine oxide. It was found that the title phosphine oxide is a racemic crystal-forming compound, and the recrystallization of the enantiomeric mixtures could be used for the preparation of pure enantiomers. According to our best method, the (R)-ethyl-(2-methylphenyl)-phenylphosphine oxide could be obtained with an enantiomeric excess of 99% and in a yield of 47%. Complete racemization of the enantiomerically enriched phosphine oxide could be accomplished via the formation of a chlorophosphonium salt. Characterization of the crystal structures of the enantiopure phosphine oxide was complemented with that of the diastereomeric intermediate. X-ray analysis revealed the main nonbonding interactions responsible for enantiomeric recognition.

Axially chiral Ni(II) complexes of α-amino acids: Separation of enantiomers and kinetics of racemization


Herein we present design, synthesis, chiral HPLC resolution, and kinetics of racemization of axially chiral Ni(II) complexes of glycine and di-(benzyl)glycine Schiff bases. We found that while the ortho-fluoro derivatives are configurationally unstable, the pure enantiomers of corresponding axially chiral ortho-chloro-containing complexes can be isolated by preparative HPLC and show exceptional configurational stability (t1/2 from 4 to 216 centuries) at ambient conditions. Synthetic implications of this discovery for the development of new generation of axially chiral auxiliaries, useful for general asymmetric synthesis of α-amino acids, are discussed. Pure enantiomers of the axially chiral ortho-chloro-containing complexes show exceptional configurational stability (t1/2 from 4 to 216 centuries) at ambient conditions.

Effects of metalaxyl enantiomers stress on root activity and leaf antioxidant enzyme activities in tobacco seedlings


The objective of this experiment was to study the effects of metalaxyl enantiomers on the activity of roots and antioxidative enzymes in tobacco seedlings. Water culture experiment was conducted to analyze the effects of different concentrations of metalaxyl enantiomers (30 and 10 mg L−1) on root activity and leaf superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities and malondialdehyde (MDA) content of tobacco seedlings. The results showed that metalaxyl significantly inhibited root activity and significantly improved leaf SOD, POD, and CAT activities and MDA content. A better physiological response in tobacco seedlings was observed at 30 mg L−1 than at 10 mg L−1 metalaxyl. The stereoselectivity for different enantiomers had no obvious effect on root activity and the leaf POD activity, but it affected significantly the SOD and CAT activities and MDA content. The SOD activity was promoted more by R-enantiomer than by S-enantiomer at 30 mg L−1 metalaxyl, and the same effect was observed on CAT activity from the beginning to the end of the stress period. The MDA content under the stress by R-enantiomer was higher than that under the stress by S-enantiomer at 10 mg L−1 metalaxyl.

Chiral separation of novel iminonaringenin derivatives


A series of 4-iminonaringenin derivatives 2-6 have been prepared in good overall yields from a condensation reaction between naringenin and primary amines. The structures of all products were confirmed by ultraviolet, infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques. These derivatives were analyzed by high-performance liquid chromatography using polysaccharide-based chiral stationary phases, namely, Chiralpak IB and Chiralcel OD, using various mobile phases. 2-Propanol showed a high enantioselectivity for naringin and its derivatives using achiral column containing immobilized polysaccharides (Chiralpak IB).

Revisiting empirical rules for the determination of the absolute configuration of cascarosides and other (ox-)anthrones


The introduction of the C10-stereocenter of (ox-)anthrones by plant organisms is not stereospecific. Consequently, often, both (10S)- and (10R)-diastereomers can be found in the same plant. Motivated by the importance of a correct assignment of the configuration at C10, this study revisits the nuclear magnetic resonance and electronic circular dichroism-based empirical rules for the determination of the absolute configuration by molecular dynamic simulations and electronic circular dichroism spectrum calculations. Furthermore, a vibrational circular dichroism spectroscopic characterization of these large and conformationally very flexible molecules reveals spectral signatures, which can be used to specifically distinguish the C10 stereochemistry. A detailed analysis of the underlying vibrational modes suggests that the observed spectral pattern of the investigated cascarosides may be generally characteristic for the C10-stereocenter of (ox-)anthrones and that they can be used for empirical spectra-structure correlations.

On the asymmetric autocatalysis of aldol reactions: The case of 4-nitrobenzaldehyde and acetone. A critical appraisal with a focus on theory


Under neutral conditions, spontaneous mirror symmetry breaking has been occasionally reported for aldol reactions starting from achiral reagents and conditions. Chiral induction might be interpreted in terms of autocatalysis exerted by chiral mono-aldol or bis-aldol products as source of initial enantiomeric excesses, which may account for such experimental observations. We describe here a thorough Density Functional Theory (DFT) study on this complex and otherwise difficult problem, which provides some insights into this phenomenon. The picture adds further rationale to an in-depth analysis by Moyano et al, who showed the isolation and characterization of bis-aldol adducts and their participation in a complex network of reversible steps. However, the lack of enantiodiscrimination (ees vanish rapidly in solution) suggests, according to the present results, a weak association in complexes formed by the catalysts and substrates. The latter would also be consistent with almost flat transition states having similar heights for competitive catalyst-bound transition structures (actually, we were unable to locate them at the level explored). Overall, neither autocatalysis as once conjectured nor mutual inhibition of enantiomers appears to be operating mechanisms. Asymmetric amplification in early stages harnessing unavoidable enantiomeric imbalances in reaction mixtures of chiral products represents a plausible interpretation.

Chiroptical structure-property relations in cyclo[18]carbon and its in silico hydrogenation products


The anisotropy of the optical activity of cyclo[18]carbon (C18), fully hydrogenated C18 (C18H36), and 26 hydrogenated compounds of intermediate composition, C18H2n, n = 1,2…17, were computed. These compounds were selected because they resemble loops of wire. The maximum gyration for acetylenic and cumulenic subgroups of compounds was linearly proportional to the product of the geometric area over which the charge can circulate, multiplied by the largest separation between carbon atoms on opposing sides of the loops. These geometric quantities can be likened to transition magnetic dipole moments and transition electric dipole moments, respectively, that can be generated in electronic excitations and which contribute in the main to nonresonant optical activity. The correlation between a computed geometric product of distance and area, and a quantum chemical property, establishes that chiroptical structure-activity relationships can be well established for judiciously chosen series of comparatively large compounds.

Chiroptical properties of 2,2’-bioxirane


The two enantiomers of 2,2′-bioxirane were synthesized, and their chiroptical properties were thoroughly investigated in various solvents by polarimetry, vibrational circular dichroism (VCD), and Raman optical activity (ROA). Density functional theory (DFT) calculations at the B3LYP/aug-cc-pVTZ level revealed the presence of three conformers (G+, G−, and cis) with Gibbs populations of 51, 44, and 5% for the isolated molecule, respectively. The population ratios of the two main conformers were modified for solvents exhibiting higher dielectric constants (G− form decreases whereas G+ form increases). The behavior of the specific optical rotation values with the different solvents was correctly reproduced by time-dependent DFT calculations using the polarizable continuum model (PCM), except for the benzene for which explicit solvent model should be necessary. Finally, VCD and ROA spectra were perfectly reproduced by the DFT/PCM calculations for the Boltzmann-averaged G+ and G− conformers.

Enantiomeric resolution and modeling of DL-alanine-DL-tryptophan dipeptide on amylose stationary phase


The enantiomeric resolution of DL-alanine-DL-tryptophan dipeptide is described on amylose stationary phase. The eluent used was CH3OH─CH3COONH4 (10mM)─CH3CN (50: 40, 10) at 0.8-mL/min flow, 230-nm detection, 25-minute run time, and 25°C ± 1°C temperature. The chiral phase was amylose [AmyCoat RP (15 cm × 0.46 cm × 5 micron)]. The magnitudes of the retention factors (k) were 2.71, 3.52, 5.11, and 7.75. The magnitudes of separation factor (α) were 1.19, 1.57, and 1.51 while the resolution factors (Rs) were 3.25, 14.84, and 15.76. The limits of detection and quantitation were of 2.5 to 5.4 and 12.8 to 27.5 μg/mL. The enantiomeric resolution is controlled by hydrogen, hydrophobic, π-π, steric, etc interactions. The elution order of the enantiomer was supported by the modeling data. The described method is fast, reproducible, precise, and selective, which can be used successfully for evaluating the enantiomers of the reported dipeptide.

Enantioseparation and identification for the rationalization of the environmental impact of 4 polychlorinated biphenyls


Polychlorinated biphenyls (PCBs) are harmful and persistent organic pollutants that have long been used in industrial manufacturing. Their persistence leads to accumulation in the food chain causing potential toxic effects. As 19 out of 78 of the chiral congeners have stable atropisomers at ambient temperature, we studied some typical enantiomers: PCB45, PCB95, PCB136, and PCB149. The chiral stationary phases OD-H and OJ-H were used for separation in analytic high-performance liquid chromatography (HPLC), as well as for collection in semi-preparative HPLC. The resolution was optimized with respect to n-hexane–based mobile phases, temperature, and flow rate. All pure enantiomers were recovered from semi-preparative HPLC within 15 minutes for practical purpose. Characterization of the absolute configurations were conducted with a combination of theoretical and experimental electronic circular dichroism measurements. The enantiomers of PCB45, PCB95, PCB136, and PCB149 proved to be eluted as R > S, S > R, R > S, and S > R, respectively. Molecular structures (eg, substituent groups) and properties (eg, bond lengths, bond angles, and dipole moments) were quantitatively analyzed to understand the toxicity effect of PCBs. In summary, we have developed a well-established methodology of collection and configuration identification for analogous PCB derivatives.

Synthesis of d-mannitol-based crown ethers and their application as catalyst in asymmetric phase transfer reactions


A few new d-mannitol-based monoaza-15-crown-5 type chiral lariat ethers and 18-crown-6 type macrocycles were synthesized. These crown compounds were used as phase transfer catalysts in asymmetric Michael addititons and in a Darzens condensation under mild conditions to afford the corresponding products in a few cases in good to excellent enantioselectivities. In the Michael addition of diethyl acetoxymalonate to trans-chalcone, in the addition of diethyl acetamidomalonate to ß-nitrostyrene, in the reaction of diethyl bromomalonate with benzylidene malononitriles, in the cyclopropanation reaction of diethyl bromomalonate and 2-benzylidene-1,3-indandione, and in the Darzens condensation of α-chloroacetophenone with benzaldehyde, maximum enantioselectivities of 39%, 65%, 99%, 56%, and 62%, respectively, were obtained in the presence of the d-mannitol-based macrocycles as the catalysts.

Lipase-catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives


Novel benzoxazole derivatives were synthesized, and their antitubercular activity against sensitive and drug-resistant Mycobacterium tuberculosis strains (M. tuberculosis H37Rv, M. tuberculosis sp. 210, M. tuberculosis sp. 192, Mycobacterium scrofulaceum, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium avium, and Mycobacterium kansasii) was evaluated. The chemical step included preparation of ketones, alcohols, and esters bearing benzoxazole moiety. All racemic mixtures of alcohols and esters were separated in Novozyme SP 435-catalyzed transesterification and hydrolysis, respectively. The transesterification reactions were carried out in various organic solvents (tert-butyl methyl ether, toluene, diethyl ether, and diisopropyl ether), and depending on the solvent, the enantioselectivity of the reactions ranged from 4 to >100. The enzymatic hydrolysis of esters was performed in 2 phase tert-butyl methyl ether/phosphate buffer (pH = 7.2) system and provided also enantiomerically enriched products (ee 88-99%). The antitubercular activity assay has shown that synthesized compounds exhibit an interesting antitubercular activity. Racemic mixtures of alcohols, (±)-4-(1,3-benzoxazol-2-ylsulfanyl)butan-2-ol ((±)-3a), (±)-4-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((±)-3b), and (±)-4-[(5,7-dibromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((±)-3c), displayed as high activity against M. scrofulaceum, M. intracellulare, M. fortuitum, and M. kansasii as commercially available antituberculosis drug-Isoniazid. Moreover, these compounds exhibited twice higher activity toward M. avium (MIC 12.5) compared with Isoniazid (MIC 50). A series of new benzoxazole derivatives with antitubercular activity was synthesized. Racemic mixtures of alcohols and esters were separated in lipase-catalyzed transesterification and hydrolysis, respectively. The most selective enzyme was Novozyme SP 435 (E > 100). The synthesized racemic mixtures of alcohols exhibited twice higher activity toward Mycobacterium avium (MIC 12.5) compared with Isoniazid (MIC 50).

Enantiomeric separation of type I and type II pyrethroid insecticides with different chiral stationary phases by reversed-phase high-performance liquid chromatography


The enantiomeric separation of type I (bifenthrin, BF) and type II (lambda-cyhalothrin, LCT) pyrethroid insecticides on Lux Cellulose-1, Lux Cellulose-3, and Chiralpak IC chiral columns was investigated by reversed-phase high-performance liquid chromatography. Methanol/water or acetonitrile/water was used as mobile phase at a flow rate of 0.8 mL/min. The effects of chiral stationary phase, mobile phase composition, column temperature, and thermodynamic parameters on enantiomer separation were carefully studied. Bifenthrin got a partial separation on Lux Cellulose-1 column and baseline separation on Lux Cellulose-3 column, while LCT enantiomers could be completely separated on both Lux Cellulose-1 and Lux Cellulose-3 columns. Chiralpak IC provided no separation ability for both BF and LCT. Retention factor (k) and selectivity factor (α) decreased with the column temperature increasing from 10°C to 40°C for both BF and LCT enantiomers. Thermodynamic parameters including ∆H and ∆S were also calculated, and the maximum Rs were not always obtained at lowest temperature. Furthermore, the quantitative analysis methods for BF and LCT enantiomers in soil and water were also established. Such results provide a new approach for pyrethroid separation under reversed-phase condition and contribute to environmental risk assessment of pyrethroids at enantiomer level.

Chemical chiral pollution: Impact on the society and science and need of the regulations in the 21st century


The chiral pollution is a serious issue for our health and environment due to the enantio-selective biodegradation of the chiral pollutants. It has adverse impact on our society and science. There is a big loss of our economy due to the use of racemic agrochemicals. The most notorious chiral pollutants are pesticides, polychloro biphenyls, polyaromatic hydrocarbons, brominated flame retardants, drugs, and pharmaceuticals. More than 1500 chiral pollutants are present in the environment. Unfortunately, there is no regulation and control of the chiral pollutants. Therefore, it is an urgent need of the present 21st century to develop a data bank on the chiral pollutants, guidelines for controlling the production, sale and use of the racemic agrochemicals and the other industrial products. The Governments of the different countries should come forward to initiate the regulations. US, FDA, US EPA, and WHO are the most important regulatory authorities and should think about the chiral pollutants. The present article highlights the impact of the chiral pollution on the society and science. Besides, the efforts have also been made to emphasize the need of the regulations to control the chiral pollution.

Left-handed helical polymer resin nanotubes prepared by using N-palmitoyl glucosamine


Although the preparation of single-handed helical inorganic and hybrid organic-inorganic nanotubes is well developed, approaches to the formation of single-handed organopolymeric nanotubes are limited. Here, left-handed helical m-phenylenediamine-formaldehyde resin and 3-aminophenol-formaldehyde resin nanotubes were prepared by using N-palmitoyl glucosamine that can self-assemble into left-handed twisted nanoribbons in a mixture of methanol and water. In the reaction mixture, the helical pitch of the nanoribbons decreased with increasing reaction time. The resin nanotubes were obtained after removing the N-palmitoyl glucosamine template, and circular dichroism spectroscopy indicated that the organopolymeric nanotubes had optical activity. Carbonaceous nanotubes were then prepared by carbonization of the 3-aminophenol-formaldehyde resin nanotubes.

Cover Image, Volume 30, Issue 3


The cover image, by Lukáš Severa et al., is based on the Short Communication Dutch Resolution of a configurationally stable [5]helquat, DOI: 10.1002/chir.22789. Background Image Credit: Dr. Paul E. Reyes-Gutiérrez.

Issue Information


No abstract is available for this article.

Chirality of 20-membered unclosed cryptand: Macroring distortion via lariat arm modification


Some of 19-membered unclosed cryptands were recognized as chiral species in a solid state. While, in terms of 20-membered macrocycle, we tune the lariat arm, developing the synthesis of α- and β-naphthyl terminated moieties to gain the structural control over chirality phenomena of these systems. Indirect synthetic approach delineates the way to reach both target structures. Solely, macrocycle functionalized with the β-naphthyl group is capable of desirable interactions with the frame of entity inducing its stronger bending that leads to the chiral crystals formation. Their structural features were examined by single crystal X-ray diffraction and chiroptical method, represented by ECD/UV spectroscopy.

Fluorescence detected linear dichroism spectroscopy: A selective and sensitive probe for fluorophores in flow-oriented systems


Fluorescence detection typically enhances sensitivity and selectivity for fluorescent analytes. The potential for combining fluorescence detection with flow orientation of the sample in the normal configuration of linear dichroism experiments is explored in this work by measuring the fluorescence emitted from flow-orientated DNA-bound ligands and M13 bacteriophage. Data for ethidium bromide, Hoechst 33258, and 4,6-diamidino-2-phenyindole are presented. The theoretical basis of the technique is also presented for instruments running in both the fixed direct-current mode, which is the normal operation mode of circular dichroism spectropolarimeters, and also in fixed high-tension voltage mode. The role of the stray light reaching the detector that results in a spectral shape in fixed direct current mode that resembles the shape of a linear dichroism spectrum, rather than the expected reduced linear dichroism, is also explored.

Mini review: Instrumentation for vibrational circular dichroism spectroscopy, still a role for dispersive instruments


Vibrational circular dichroism (VCD) has become a standard method for determination of absolute stereochemistry, particularly now that reliable commercial instrumentation has become available. These instruments use a now well-documented Fourier transform infrared-based approach to measure VCD that has virtually displaced initial dispersive infrared-based designs. Nonetheless, many papers have appeared reporting dispersive VCD data, especially for biopolymers. Instrumentation designed with these original methods, particularly after more recent updates optimizing performance in selected spectral regions, has been shown still to have advantages for specific applications. This article presents a mini-review of dispersive VCD instrument designs and includes sample spectra obtained for various biopolymer (particularly peptide) samples. Complementary reviews of Fourier transform-VCD designs are broadly available.

Dutch Resolution of a configurationally stable [5]helquat


Synthesis and nontrivial optical resolution of a helicene-like dication, helquat 1, has been accomplished. Starting with gram scale of the racemic helquat 1 sample, Dutch Resolution using family of 3 tartrate anions was key to achieve successful separation of M and P helical enantiomers of 1. Hundreds of milligrams of each enantiomer of this configurationally stable C2-symmetric helquat have been obtained. Racemization barrier of 1 has been determined. To our knowledge this is the first report on Dutch Resolution performed with a helicene-like compound. Moreover, there are no literature precedents for Dutch Resolution of chiral quaternary ammonium cations. Racemic helquat 1 has been resolved by using Dutch Resolution. Using family of three tartrate anion derivatives, hundreds of milligrams of each enantiomeric salt, [P-1][Br]2 and [M-1][Br]2, have been obtained in high optical purity (98% ee). This is the first report on Dutch Resolution performed with a helicene-like compound as well as the first such resolution with chiral quaternary ammonium cation.

Circular dichroism of surface complexes based on quantum dots and azo dye


Chiral properties of surface complexes based on CdSe/ZnS quantum dots (QDs) and 1-(2-pyridylazo)-2-naphthol (PAN) azo dye were investigated by circular dichroism spectroscopy. The use of L-, D-cysteine (Lcys, Dcys) capping ligands allowed us to obtain water-soluble chiral QD-PAN complexes. The characterization of the complexes was performed by UV-vis, FTIR, and CD spectroscopy. Quantum chemical TDDFT calculated CD spectra reproduced the experimentally observed sign patterns, which originate from binding Lcys or Dcys and PAN molecules to the same Zn atom on the QD surface. The resulting complex is characterized by a large circular dichroism in comparison with an ordinary QD chirality induced by cysteine molecules. The pattern of CD signal is the same for Lcys and Dcys ligands in chiral QD-PAN complex. Schematic representation of chiral Dcys-ZnSH-PAN complex.

Efficient resolution of venlafaxine and mechanism study via X-ray crystallography


Numbers of resolving factors were investigated to improve resolution of venlafaxine 1. An effective resolving agent, O,O′-di-p-toluoyl-(R, R)-tartaric acid 2, was screened using similar method of ‘Dutch resolution’ from tartaric acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of rac-1 and 2 was 1:0.8 in THF with little water (10:1 v/v). Enantiomerically pure venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution mechanism was first explained through X-ray crystallographic study. One diastereomeric salt with well solubility forms a columnar supramolecular structure as the acidic salt (R)-1·2, while the other diastereomeric salt with less solubility forms a multilayered sandwich supramolecular structure by enantio-differentiation self-assembly as the neutral salt 2(S)-1·2. The water molecules play a key role in the optical resolution, as indicated by the special structures of the diastereomeric salts.

Enantioselective recognition of carboxylic acids by novel fluorescent triazine-based thiazoles


Hydrogen bonding and π-π interactions take special part in the enantioselectivity task. In this regard, because of having both hydrogen acceptor and hydrogen donor groups, melamine derivatives become more of an issue for enantioselectivity. In the light of such information, triazine-based chiral, fluorescence active novel thiazole derivatives L1 and L2 were designed and synthesized from (S)-(−)-2-amino-1-butanol and (1S,2R)-(+)-2-amino-1,2-diphenylethanol. The structural establishment of these compounds was made by spectroscopic methods such as FTIR, 1H, and 13C NMR. While the solution of these compounds in DMSO did not show any fluorescence emission, it was observed that the emission increased 44-fold for L1 and 55-fold for L2 in 95% water, similar to the aggregation-induced emission (AIE) characterized compounds. In this regard, enantioselective capabilities of these compounds against carboxylic acids were tested, and in experiments carried out at a ratio of 40/60 DMSO/H2O, it was determined that R-2ClMA increased the fluorescence emission of L1 chiral receptor by 2.59 times compared to S-isomer.

Liquid chromatographic separation and thermodynamic investigation of lorcaserin hydrochloride enantiomers on immobilized amylose–based chiral stationary phase


A novel liquid chromatographic method was developed for enantiomeric separation of lorcaserin hydrochloride on Chiralpak IA column containing chiral stationary phase immobilized with amylose tris (3.5-dimethylphenylcarbamate) as chiral selector. Baseline separation with resolution greater than 4 was achieved using mobile phase containing mixture of n-hexane/ethanol/methanol/diethylamine (95:2.5:2.5:0.1, v/v/v/v) at a flow rate of 1.2 mL/min. The limit of detection and limit of quantification of the S-enantiomer were found to be 0.45 and 1.5 μg/mL, respectively; the developed method was validated as per ICH guideline. The influence of column oven temperatures studied in the range of 20°C to 50°C on separation was studied; from this, retention, separation, and resolution were investigated. The thermodynamic parameters ΔH°, ΔS°, and ΔG° were evaluated from van't Hoff plots,(Ink′ versus 1/T) and used to explain the strength of interaction between enantiomers and immobilized amylose–based chiral stationary phase

The influence of microbial communities for triadimefon enantiomerization in soils with different pH values


Enantiomers of chiral molecules can undergo interconversion leading to markedly different toxicities, which can introduce significant uncertainty when evaluating biological and environmental fates. However, enantiomerization (the reversible conversion of one enantiomer into the other) related to soil microorganism is rarely understood. For better understanding, S-triadimefon and R-triadimefon enantiopure were incubated in different soils with different pH value. Both high-performance liquid chromatography and high-throughput sequencing technology were used to explore target analytes quantitatively and microbial taxa related to the conversion process. Results revealed a significant enantiomerization among the soils. The alkaline soil from Beijing had a faster conversion than neutral soil from Changchun, while acidic soil from Wuhan had no conversion. At the same results, analysis of bacteria community showed higher abundance of Arthrobacter and Halomonas genus in alkaline soil than neutral soil after treatments, but the acidic soil was lower. Moreover, Arthrobacter and Halomonas were responsible for converting S-triadimefon to R-triadimefon and R-triadimefon to S-triadimefon in alkaline and neutral soil, respectively. Thus, these genera may be one of the reasons to explain the enantiomerization in different soils observed in this study. Thus, research at microbial level is necessary for efficient ecological risk assessment of chiral fungicide.

Supramolecular solvent-based vortex-mixed microextraction: Determination of chiral triazole fungicide in beer samples


A supramolecular solvent composed of decanol in tetrahydrofuran/water was utilized for the simultaneous microextraction of chiral triadimefon and triadimenol in beer samples. Supramolecular solvents are nanostructured amphiphilic liquids that contain aqueous cavities, and the size of those cavities can be adjusted by the ratio of decanol, tetrahydrofuran, and water. The target analytes were mixed into the matrix sample and extracted in the supramolecular solvent phase, which was followed by separation and quantification by chiral liquid chromatography-mass spectrometry. The influences of some analytical parameters and matrix components were all examined. Under the optimized conditions, the method detection limits were in the range of 0.24 to 0.98 μg L−1 (at a signal/noise of 3), with relative standard deviations between 1.6 and 5.7%. The linearities of the calibration plots were between 0.5 to 50 (triadimenol) and 1.0 to 100 μg L−1 (triadimefon). When this method was applied to a spiked beer sample, the recoveries ranged from 84 to 100%.

Influence of lactic acid bacteria on stereoselective degradation of theta-cypermethrin


The purpose of this study was to investigate the influence of four kinds of Lactic acid bacteria (LAB) on stereoselective degradation of theta-cypermethrin (CYP), including Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii, and Streptococcus thermophilus. An effective analytical method for (±)-theta-CYP in medium was developed by high-performance liquid chromatography with cellulose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase. theta-Cypermethrin was spiked to LAB medium with different inoculation rates and sampled at 0, 2, 8, 24, 36, 48, 72, 120, 168, and 240 hours. The results showed that LAB influenced the half-lives and enantiomer fractions of theta-CYP enantiomers, which lead a closer degradation rate between the 2 stereoisomers, and no obvious difference was found among 4 LABs. Besides, the stereoselective degradation of theta-CYP was closely related to pH. The lower the pH (pH of 3, 5, 7, and 9), the lower the enantiomer fraction (from 4.88 to 6.69). At pH of 3, 7, and 9, significant differences of half-lives between enantiomers were observed. (−)-theta-Cypermethrin decreased faster than (+)-theta-CYP under pH of 3, while opposite results were indicated under pH of 7 and 9. Moreover, the acidic condition contributed to the higher chiral configuration stability of (±)-theta-CYP. (+)-Enantiomer was influenced by pH in a greater degree than (−)-enantiomer.